Is CROT p.Arg451His (c.1352G>A) pathogenic?

CROT p.Arg451His (c.1352G>A) is classified Uncertain significance in CROT (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-23). AlphaMissense: likely pathogenic (0.9315); Ultra-rare (popmax 0.0169%, amr).

How common is CROT p.Arg451His (c.1352G>A) in the general population?

CROT p.Arg451His (c.1352G>A) is ultra-rare (popmax 0.0169%, amr) (gnomAD).

What do computational predictors say about CROT p.Arg451His (c.1352G>A)?

AlphaMissense predicts likely pathogenic (score 0.9315) — an in-silico prediction, not a clinical call.

CROT p.Arg451His

c.1352G>A · rs146906054 · VCV2406776

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9315 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9315	likely pathogenic
REVEL	0.925	moderately pathogenic-leaning
SaProt	LLR -15.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 9.9	GERP 0.74, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 50 kb · p 0.53 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0169% Admixed American · 10/59,242 alleles

Filtering AF 0.00911% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00689%

Overall 0.0023% 37/1,610,536 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0169%	5,924
African / African-American	0.0067%	14,928
East Asian	0.00224%	44,710
South Asian	0.00221%	45,160
Remaining individualsnot grpmax-eligible	0.0016%	62,314
European (non-Finnish)	0.00153%	65,491

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CROT
Protein: p.Arg451His
Coding: c.1352G>A
MANE Select: NM_000443 · reported on NM_021151
dbSNP: rs146906054
Type: single nucleotide variant
Location: chr7:87391639 (GRCh38)

Full CROT gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/crot-p-arg451his (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown